Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis - PubMed (original) (raw)

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Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis

Pablo J Fernandez-Marcos et al. Am J Clin Nutr. 2011 Apr.

Abstract

Mechanisms responsible for energy management in the cell and in the whole organism require a complex network of transcription factors and cofactors. Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) has emerged as a master regulator of mitochondrial biogenesis and function, thus becoming a crucial metabolic node. We present an overview of the mechanisms by which PGC-1α is regulated, including the transcriptional regulation of PGC-1α expression and the fine-tuning of its final activity via posttranslational modifications.

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Figures

FIGURE 1.

FIGURE 1.

Regulation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) transcription. At the PGC-1α promoter, there are binding sites for transcription factors myocyte enhancer factor 2 (MEF2), forkhead box class-O (FoxO1), activating transcription factor 2 (ATF2), and cAMP response element–binding protein (CREB), all of which enhance PGC-1α transcription. These factors, in turn, are modulated by different signaling pathways: insulin activates Akt, which leads to cytoplasmic sequestration and inhibition of FoxO1; cytokines and exercise activate p38 mitogen-activated protein kinase (p38MAPK), which phosporylates and activates MEF2 and ATF2; exercise also stimulates Ca2+ signaling, which, through calmodulin-dependent protein kinase IV (CaMKIV) and calcineurin A (CnA), will induce CREB and MEF2-mediated PGC-1α transcription; and cold activates β3-adrenergic receptors (β3-AR) in muscle and brown fat, leading to protein kinase A (PKA)–mediated activation of CREB. IRS, insulin response sequence; GLGN-R, glucagon receptor; P, phosphate; CRE, cAMP response element.

FIGURE 2.

FIGURE 2.

Posttranslational modifications of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Numerous modifications have been described to affect PGC-1α, modulating its levels and activity through phosphorylation, acetylation, methylation, ubiquitination, and _O_-linked N_-acetylglucosylation. The respective residues or regions where these modifications occur are indicated. Certain modification sites are mapped in the mouse or the human PGC-1α protein (as indicated in the key). AMPK, AMP-activated protein kinase; PKA, protein kinase A; p38MAPK, p38 mitogen-activated protein kinase; GSK3β, glycogen synthase kinase 3_β; SCFCdc4, Skp1/Cullin/F-box cell division control 4; OGT, _O_-linked _N_-acetylglucosamine transferase; Clk2, Cdc2-like kinase 2; Ac, acetylation; CPD, Cdc4 phosphodegron; SR, serine-arginine domain; GCN5, general control of amino acid synthesis 5; Sirt1, silence information regulator 2-like 1; PRMT1, protein arginine methyltransferase 1.

FIGURE 3.

FIGURE 3.

Cellular sensing of energy status through acetylation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). In situations of low energy status, AMP-activated protein kinase (AMPK)–increased NAD+ amounts enhance Sirt1 activity and lead to the activating deacetylation of PGC-1α and increased mitochondrial biogenesis and function. When energy is abundant in the cell, GCN5 (general control of amino acid synthesis) acetylates and inhibits PGC-1α; the acetyl-CoA necessary for this reaction is provided by ATP-citrate lyase (ACL), which acts as a rate-liming factor for GCN5-mediated acetylation of PGC-1α. Ac, acetylation.

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